Process for the preparation of 5-amino-1,3-dioxanes

ABSTRACT

A process for the preparation of 5-amino-1,3-dioxanes of formula (I), comprising the catalytic hydrogenation of the new oximes of formula (II) is described.

This is a Division of application Ser. No. 08/722,174, filed on Oct. 10,1996, now U.S. Pat. No. 5,663,372, which was filed as InternationalApplication No. PCT/EP95/01246 on Apr. 5, 1995.

The present invention relates to a process for the preparation ofacetals of 2-amino-1,3-propanediol and, more particularly, it relates toa process for the preparation of 5-amino-1,3-dioxanes. The acetals of2-amino-1,3-propanediol are advantageously used as syntheticintermediates in the preparation of the compound (S)-N,N'-bis-2-hydroxy-1-(hydroxymethyl)ethyl!-5-(2-hydroxy-1-oxopropyl)amino!-2,4,6-triiodo-1,3-benzenedicarboxamide,known with its International Nonproprietary Name Iopamidol (The MerckIndex, XI Ed., page 799, No. 4943).

Iopamidol was described for the first time by the Swiss Company SavacA.G. in the British patent No. 1,472,050 and is used in diagnostics as anon-ionic X-ray contrast medium. The preparation of Iopamidol, describedin said patent, comprises the condensation reaction ofL-5-(2-acetoxy-propionylamino)-2.4,6-triiodo-isophthalic acid dichloridewith 2-amino-1,3-propanediol, better known as serinol, indimethylacetamide and in the presence of a base.

Alternatively, in the same patent, a method comprising the condensationreaction of the above acid dichloride with an acetal of serinol isdescribed; the subsequent acid hydrolysis of the resultant diacetal,carried out according to conventional techniques, allows then to obtainthe desired product. Among the possible acetals of serinol which can beused in said synthesis, for instance, 5-amino-1,3-dioxanes are cited.Several processes for the preparation of 5-amino-1,3-dioxanes arereported in the literature.

The British patent application No. 2,081,256 (Rhone-Poulenc Industries)and the U.S. Pat. No. 3,812,186 (Eprova A.G.) describe the preparationof 5-amino-2,2-dialkyl-1,3-dioxanes by catalytic hydrogenation of thecorresponding 5-nitro derivatives which, in turn, are prepared by directcyclization of 2-nitro-1,3-propanediol with a suitable ketone, in thepresence of boron trifluoride etherate.

In the U.S. Pat. No. 4,978,793 (W.R. Grace & Co.) it is described apreparation of 5-amino-2,2-dialkyl-1,3-dioxanes which comprises at firstthe synthesis of the corresponding 5-nitro derivatives, through a threestep process starting from nitromethane and formaldehyde, and,subsequently, the reduction of the nitro group. The processes for thepreparation of 5-amino-1,3-dioxanes described in the literature evidencethe remarkable drawback of using nitro derivatives, which areparticularly unstable and explosive compounds, as intermediates.

Processes for the preparation of primary amines comprising the reductionof the corresponding oximes are also known in the literature.

Said reductions can be carried out by using conventional reducing agentsor by means of catalytic hydrogenation M. Hudlicky, Reduction in OrganicChemistry, Academic Press, (1984)!. Nevertheless, to the extent of ourknowledge, the preparation of acetals of serinol through the reductionof the corresponding oximes has been never described in the literature.

Now we have found and it is the object of the present invention aprocess for the preparation of 5-amino-1,3-dioxanes of formula ##STR1##

wherein

R and R₁, the same or different, represent a hydrogen atom, a straightor branched C₁ -C₄ alkyl, an optionally substituted phenyl or, togetherwith the carbon atom to which they are bonded, form a C₅ -C₆cycloaliphatic ring, comprising the reduction of the oximes of formula##STR2## wherein R and R₁ have the above reported meanings, by catalytichydrogenation in a suitable solvent.

The compounds of formula I can be optionally hydrolyzed to serinolaccording to conventional techniques. Either the serinol or the aminoacetals of formula I are useful intermediates in the preparation ofIopamidol as described, for instance, in the aforementioned Britishpatent No. 1,472,050.

With the term acetal, we intend a compound obtained by reacting analcohol, or even a diol, with either a ketone or an aldehyde (IUPACNomenclature of Organic Chemistry, 1979-Edition, Rule C-331, page 178).

With the term catalytic hydrogenation we intend a reduction reactioncarried out in the presence of catalysts, wherein the reducing agent ishydrogen (J. March, Advanced Organic Chemistry, IV Ed., 1026).

The process object of the present invention is of easy industrialapplication and the compounds of formula I and II, being stable, do notpresent the risk of explosions during the accomplishment of t:heprocess.

Specific examples of the compounds of formula I obtainable according tothe process object of the present invention are:

5-amino-2,2-dimethyl-1,3-dioxane

5-amino-2,2-diethyl-1,3-dioxane

5-amino-2-ethyl-2-methyl-1,3-dioxane

5-amino-2-phenyl-1,3-dioxane

3-amino-1,5-dioxaspiro 5,5!undecane

3-amino-1,5-dioxaspiro 4,5!decane

The 1,3-dioxan-5-one oximes of formula II are new and they are a furtherobject of the present invention.

Said compounds can be prepared by direct acetalization of1,3-dihydroxyacetone oxime with a ketone or with an aldehyde in thepresence of an acid.

It is clear to the man skilled in the art that the meanings of both Rand R₁ substituents, for the compounds of formula I and II, will dependon the selected aldehyde or ketone.

In this connection, it is worth noting that, since the use to which thecompounds of formula I are intended comprises their hydrolysis with lossof the R-CO-R₁ fragment, the nature of the groups R and R₁ is of littleimportance and their selection will be substantially guided by economicand availability criteria.

Specific examples of aldehydes or ketones which can be used in the aboveacetalization reaction are, for instance, formaldehyde, acetaldehyde,benzaldehyde, 4-methoxybenzaldehyde, 2-methylbenzaldehyde, acetone,butanone, 2-pentanone, 3-pentanone, cyclopentanone, cyclohexanone,acetophenone and benzophenone. Alternatively, the preparation of1,3-dioxan-5-one oximes of formula II can be carried out, in a preferredway, by reacting the corresponding 1,3-dioxan-5-ones with hydroxylaminehydrochloride, according to the methods usually adopted in thepreparation of the oximes (J. March, Advanced Organic Chemistry, IV Ed.,906-907).

The above 1,3-dioxan-5-ones are known compounds and are preparedaccording to known methods D. Hoppe et al., Tetrahedron, 45 (3),687-694, (1989)!.

The oximes of formula II according to the process object of the presentinvention are then catalytically hydrogenated to the compounds offormula I, in the presence of suitable reaction solvents.

Examples of employable catalysts are those commonly used in thereactions of catalytic hydrogenation.

Preferably, rhodium on alumina, Raney nickel and palladium on charcoalare used.

The catalyst is used in amounts preferably comprised between 0.001 and0.01 moles per mole of substrate to be hydrogenated, i.e. the selected1,3-dioxan-5-one oxime of formula II.

Larger amounts of catalyst, for instance up to 10-15% in moles withrespect to the substrate, can also be used.

The hydrogenation reaction according to the process object of thepresent invention is carried out, as previously pointed out, in thepresence of suitable inert solvents.

With the term inert solvents we intend the solvents which do not undergochemical reactions with the reagents or with the reaction products.

Suitable solvents are those commonly used in the reactions of catalytichydrogenation such as, for instance, lower C₁ -C₄ alcohols. Methanol andethanol are preferably used.

Pressure and temperature do not represent critical parameters of thereaction.

Preferably, the hydrogenation is carried out at a pressure comprisedbetween 1 and 10 bars (10⁵ -10⁶ Pa) and at a temperature comprisedbetween 20° C. and 80° C.

More drastic conditions of pressure and temperature are equallyeffective but useless.

In a practical embodiment, the process object of the present inventionis carried out according to the following operating conditions. Asuitable amount of the compound of formula II in a suitable solvent (forinstance methanol) is loaded into a reactor suitable to sustain internalpressures, and a suitable amount of catalyst is then added.

The resultant system is put under hydrogen atmosphere according to thecommonly used techniques and kept under stirring for a few hours (5-24)at the preselected temperature and pressure for instance 60° C. and 7bars (7·10⁵ Pa)!.

Due to the following practical features such as, for instance, the easyindustrial application, the accessibility of the starting material, thestability of the reagents and of the reaction products and the simplework-up of the reaction mixture, the present invention makes available avery advantageous process for the preparation of 5-amino-1,3-dioxanes.

With the aim to better illustrate the present invention, without howeverlimiting it, the following examples are now given.

EXAMPLE 1 Preparation of 2.2-dimethyl-1.3-dioxan-5-one oxime

Hydroxylamine hydrochloride (5 g; 71.9 mmoles) was added, under stirringand in 30 minutes, to a solution of 2,2-dimethyl-1,3-dioxan-5-one (6.2g; 47.7 mmoles) in pyridine (6.75 g; 85.4 mmols), keeping thetemperature at 150° C.

At the end, the reaction mixture was kept under stirring at 25° C. for 4hours.

Methylene chloride (30 ml) and water (15 ml) were subsequently added,maintaining the stirring for furthers 5 minutes.

The phases were separated and the organic phase, washed with water (10ml), was dried on anhydrous sodium sulphate and evaporated at reducedpressure.

2,2-Dimethyl-1,3-dioxan-5-one oxime (6.7 g) was thus obtained (97.5% ¹H-NMR titre, 95% yield).

¹ H-NMR (300 MHz, DMSO-d₄): δ(ppm): 1.33 (s, 6H); 4.19 (s, 2H); 4.46 (s,2H); 10.82 (s, 1H).

IR (NEAT): significative bands at 3360, 1440, 1380 cm⁻¹ By working in asimilar way but using 1,3-dioxan-5-one, 2,2-diethyl-1,3-dioxan-5-one and1,5-dioxaspiro 5,5!undecan-3-one, in place of2,2-dimethyl-1,3-dioxan-5-one, the following compounds were respectivelyobtained: 1.3-dioxan-5-one oxime, 2-diethyl-1.3-dioxan-5-one oxime and1.5-dioxaspiro 5.51!undecan-3-one oxime.

EXAMPLE 2 Preparation of 5-amino-2.2-dimethyl-1.3-dioxane

2,2-Dimethyl-1,3-dioxan-5-one oxime (5 g; 34.4 mmoles), prepared asdescribed in example 1, methanol (40 ml) and rhodium supported onalumina at 5% (0.35 g; 0.17 mmoles) were respectively loaded into areactor provided with mechanical stirring.

After removing the surrounding air, hydrogen at a pressure of 7 bars(7·10⁵ Pa) was added.

The resultant system was thus kept under stirring at 60° C. for 5 hours.

At the end of the reaction, after emptying the reactor, the catalyst wasfiltered off on a celite bed and the solvent was evaporated at reducedpressure.

A crude product (5 g) constituted by 5-amino-2,2-dimethyl-1,3-dioxane(65% G.C. titre, 72% yield), according to gas-chromatogranphic analysis,was thus obtained.

The desired product was then isolated by distillation of the reactioncrude at 75° C. and 12 mm/Hg.

We claim:
 1. A process for the preparation of 2-amino-1,3-propanediolcomprising reducing the oximes of formula ##STR3## wherein R and R₁, thesame of different, represent a hydrogen atom, a straight or branched C₁-C₄ alkyl, an unsubstituted substituted phenyl or, together with thecarbon atom to which they are bonded, form a C₅ -C₄ cycloaliphatic ring,by catalytic hydrogenation in a solvent, to the corresponding5-amino-1,3-dioxanes of formula ##STR4## and, subsequently, hydrolyzingthe compounds of formula I to 2-amino-1,3-propanediol.